Development of a safe vaccine program at Fred Hutchinson Cancer Research Center (FHCRC) and the University of Washington (UW), together with the Seattle community, has a long-standing commitment to HIV-1 vaccine development. We propose to join the HIV Vaccine Trials Network (HVTN) as a comprehensive FHCRC/UW HIV Vaccine Trials Unit (HVTU) that will lead and participate in clinical vaccine development through three specific aims. In Aim 1, we will provide scientific leadership to the HVTN as chair of the Lab Sciences Committee, member of the Scientific Steering Committee, head of the primary infection and mucosal working groups, and director of core laboratory studies with specific expertise in assessing vaccine- induced T cell and mucosal responses. We will also chair and participate in protocol teams to develop and oversee clinical trials. Through ancillary funding, we will conduct studies in HIV-I exposed seronegative persons, HIV-I infected patients (acute seroconverters and long-term non- progressors), and Senegalese HIV-l/2 infected patients, to gain insights concerning immune responses appropriate to elicit by vaccination. In collaboration with South African investigators, we will perform focused studies on mucosal and clade-specific T cell responses in vaccine recipients, HIV-1 exposed and HIV-infected persons of varying risk groups. In Aim 2, we will merge the collective knowledge and infrastructure from 10 years as an AVEU and 4 years as a HIVNET site to conduct phase I, II, and III clinical trials of candidate HIV-I vaccines at the FHCRC/UW HVTU and at a satellite site at the Universidad Peruana Cayetano Heredia in Lima, Peru. In Aim 3, we will expand our capabilities at the Seattle and Lima sites to recruit participants for large, multi-center efficacy trials of one or more HIV vaccine candidates. This effort will entail support from our Community Advisory Board and broad community-based education. We will comply with all federal and international regulations, network policies for reporting, and insure appropriate inclusion of new investigators, particularly women and minorities. We face many obstacles in developing a successful HIV-1 vaccine. We must continue to seek guidance from basic immunologic and virologic studies and employ good judgment in selecting immunogens for testing in small and large-scale studies. Coordinated efforts will be required among academic and governmental institutions, industry, and the international communities. We are committed to these activities as we seek a long-term solution to the HIV-1 epidemic.